1-acylamidoalkyl-benzodiazepin-2-ones

ABSTRACT

1,4-BENZODIAZEPIN-2-ONES BEARING AN ACYLAMIDOALKYLSUBSTITUENT IN THE 1-POSITION AND METHODS FOR THE PREPARATION THEREOF ARE DISCLOSED. THESE 1,4-BENZODIAZEPIN-2ONES EXHIBIT SEDATIVE, ANTI-CONVULSANT AND MUSCLE RELAXANT ACTIVITY.

United States Patent 3,772,271 l-ACYLAMIDOALKYL-BENZODIAZEPlN-Z-ONESJoseph Hellerbach, Basel, Switzerland, Armin Walser,

West Caldwell, N.J., Hermann Bretschneider, Innsbruck, Austria, andWerner Rudolph, Nuremberg, Germany, assignors to Holfmann-La Roche Inc.,Nutley,

Nb'nmwin Filed Feb. 1, 1971, Ser. No. 111,731 Claims priority,application S/witzerland, Feb. 11, 1970,

70 Int. elf 007d 53/06 US. Cl. 260239.3 D 9 Claims ABSTRACT OF THEDISCLOSURE 1,4-benzodiazepin-2-ones bearing an acylamidoalkylsubstituentin the 1-position and methods for the preparation thereof are disclosed.These 1,4-benzodiazepin-2- ones exhibit sedative, anti-convulsant andmuscle relaxant activity.

DESCRIPTION OF THE INVENTION The present invention is directed to1,4-benzodiazepin- 2-ones which exhibit sedative, anti-convulsant andmuscle relaxant activity. More particularly, the present invention isconcerned with l-substituted-l,3,-dihydro-2H1,4-benzodiazepin-Z-ones ofthe general formula wherein R signifies halogen or nitro; R signifieshydrogen or halogen; R signifies hydrogen, lower alkyl or ary; Rsignifies lower alkyl,

and the pharmacentically acceptable acid addition salts thereof.

As used herein, the term lower alkyl denotes straight or branched chainhydrocarbon groups containing from 1-7 carbon atoms, preferably 1-4carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and the like.The expression aryl denotes a phenyl residue or a halo or loweralkyl-substituted phenyl residue such as o-tolyl, mtolyl, p-tolyl,o-chlorophenyl, m-fluorophenyl, p-bromophenyl, and the like. The termhalogen denotes all four forms thereof, i.e., fluorine, chlorine,bromine and iodine, unless indicated otherwise.

Among the preferred compounds falling within the scope of Formula Iabove are those wherein the R substituent is substituted at the7-position of the benzodiazepine moiety. Likewise preferred are thosecompounds of Formula I wherein R is located in the ortho-position of theS-phenyl ring if it represents halogen. Further preferred are thecompounds of Formula I wherein the R substituent is chlorine or nitroand is located in the 7 -position of the benzodiazepine moiety; the Rsubstituent is hydrogen, chlorine or fluorine and is located in the 2-position of the benzodiazepine moiety, and the R sub- 3,772,271 PatentedNov. 13, 1973 stituent is hydrogen, methyl or phenyl, i.e., compounds ofthe formula wherein R is as above; R signifies chlorine or nitro; R

signifies hydrogen, chlorine or fluorine; R signifies hydrogen, methylor phenyl and the pharmaceutically acceptable acid addition saltsthereof.

Most preferred of the compounds of Formula I above are:

Ethyl- (2,3-dihydro-7-nitro-2-oxo-5-phenyl-1H-1,4-benzodiazepin- 1-ylmethyl] carbamate;

Ethyl- (7-chloro-2,3-dihydro-2-oxo-5-phenyl-1'H- 1,4-benzodiazepinl-ylmethyl] carbamate;

Ethyl-{ [7 -chloro-5 2-chlorophenyl -2,3-dihydro-2-oxo- 1H- 1,4-benzodiazepinl-yl] methyl} carbamate;

Ethyl- [a- (7-chloro-2,3-dihydro-2-oxo-S-phenyl-1H-1-,4-

benzodiazepin-1-yl)benzyl]carbamate;

Ethyl-[1-(7-chloro-2,3-dihydro-2-oxo-S-phenyl-1H-l,4-

benzodiazepinl-yl) ethyl] carbamate.

The novel compounds of Formula I above can be prer pared following avariety of procedures.

(A) In one process aspect of the present invention, the compounds ofFormula I may be prepared by reacting a compound of the formula whereinR and R are as described above,

with a compound of the formula R5-S 0z0N-COOR4 HzRa III wherein R and Rare as described above and R signifies lower alkyl or aryl,

in the presence of a base.

The reaction between the compounds of Formulae II and Ill above isexpediently eflected in the presence of an anhydrous polar aproticsolvent such as dimethylformamide and like solvents. Preferred bases forthe purposes of this process aspect include tertiary aliphatic aminessuch as triethylamine. Although temperature and pressure are notcritical to this process aspect, it is preferable to effect the reactionat elevated temperatures, most preferably, at the reflux temperature ofthe reaction medium.

The R substituent in the compounds of'Formula III can be, for example,methyl, ethyl, phenyl, p-bromophenyl, or p-tolyl. Examples of compoundsof Formula III suitable for the process include ethyl(N-methyl-N-ptoluenesulfonyloxy)carbamate, ethyl (N-benzyl-N-p- HONC oR4 CHz-R wherein R and R are as described above,

with a reactive derivative of a sulfonic acid of the general formula RSO OH wherein R is as described above.

As reactive derivatives of the sulfonic acids of Formula V, preferredare the halides, primarily the chlorides (such as p-toluenesulfonylchloride). N-methyl-N-carbethoxyhydroxylamine,N-benzyl-N-carbethoxyhydroxylamine, N- ethyl-N-carbethoxyhydroxylamine,and the like is, for example, used as the compound of Formula IV. Thereaction conditions largely depend on the nature of the sulfonic acidderivative employed as the acylating agent. Thus, for example, theacylation is with advantage carried out in pyridine when an acid halideis used as the acylating agent.

The compounds of Formula III above can be used not only for the purposesof this process aspect of the invention, but in addition asintermediates in many phases of preparative organic chemistry. Forexample, these compounds can be used generally for N-substitution ofprimary and secondary amides with the residue wherein R and R are asdescribed above. In reacting the compound of Formula III with the amideto be substituted, the reaction is effected in the presence of a base.This reaction is expediently effected in the presence of an anhydrouspolar aprotic solvent such as dimethylformamide and like solvents.Preferred bases for this purpose include tertiary aliphatic amines suchas triethylamine. Although temperature and pressure are not critical tothe successful performance of this reaction, it is preferable to effectthe reaction at elevated temperatures, most preferably at the refluxtemperature of the reaction medium.

The compounds of the above Formula IV are known or are accessibleaccording to known processes, for example, by reaction of thecorresponding hydroxylamines of the formula R CH -NHOH wherein R is asdescribed above,

with a lower alkyl ester of chloroformic acid.

(B) In a second process aspect of the present invention, the compoundsof Formula I can be prepared by cyclizing a compound of the generalformula wherein R R R and R are as described above.

The cyclization of the compound of Formula VII is readily effected inthe presence of an inert organic solvent. Suitable solvents for thispurpose include lower alkanols, such as methanol, ethanol, and the like,ethers such as dioxane, tetrahydrofuran, and the like, amides such asdimethylformamide, and the like. The cyclization reaction can also beeffected in an aqueous medium. In a preferred embodiment of this processaspect, a solution, especially an aqueous solution of a suitable acidaddition salt (i.e., the hydrochloride) of the compound of Formula VIIis made neutral to alkaline, for example, by addition of sodiumcarbonate solution, whereupon spontaneous cyclization to thecorresponding derivative of Formula I is effected.

Examples of compounds of Formula VII suitable for this process aspectinclude2-amino-N-[(ethoxycarbonylamino)methyl]2-benzoyl-4'-chloroacetanilide,2-amino- N [(ethoxycarbonylamino)methyl] 2' benzoyl 4 nitroacetanilide,2 amino N [(ethoxycarbonylamino) methyl] 4' chloro 2 (ochlorobenzoyl)acetanilide, 2 amino N [oz (ethoxycarbonylamino)benzyl] 2'benzoyl-4'-chloroacetanilide, 2-amino-N-l-(ethoxycarbonylamino)ethyl]-2'-benzoyl4'-chloroacetanilide and thelike.

The compounds of Formula VII above used as starting materials in thisprocess aspect of the present invention can be prepared by reacting acompound of the formula (VIII) wherein R and R are as described above,and X signifies any suitable protecting group,

with a compound of Formula III above in the presence of a baseandsubsequently splitting off the protecting group. A suitableprotecting group for this purpose is a carbobenzoxy group which can beremoved hydrogenolytically, for example, by hydrogen in the presence ofa palladium catalyst. If the removal of the protecting group is effectedin an acidic medium there results the acid addition derivative of thecompound of Formula VII. If removal of the protecting group is effectedin neutral or alkaline medium, cyclization of the Formula VII compoundoccurs spontaneously resulting in the corresponding compound of FormulaI.

The reaction between the compounds of Formulae HI and VIII isexpediently effected in the presence of a base and an anhydrous polaraprotic solvent such as dimethylformamide and like solvents. Suitablebases for this purpose include tertiary aliphatic amines such astriethylamine. It is preferable to conduct this reaction at elevatedtemperatures, most preferably at the reflux temperature of the reactionmedium.

The benzodiazepine derivatives of Formula I are basic in nature and canbe converted into their pharmaceutically acceptable acid addition saltsby reaction with organic or inorganic acids. Examples of acids whichform pharmaceutically acceptable salts are hydrogen chloride, hydrogenbromide, sulfuric acid, acetic acid, maleic acid, methanesulfonic acid,p-toluenesulfonic acid, and the like.

The compounds of Formula I above exhibit sedative, anti-convulsant andmuscle relaxant properties. The anticonvulsant activity of thesecompounds may be demonstarted by employing standard techniques. Forexample, the 'anti-convulsant activity can be shown by subjecting miceto which a compound of Formula I or a salt thereof has been administeredto the pentamethylene tetrazole test following the method disclosed byOrloff [Proc. Soc. Exptl. Biol. Med. 70, 254-257 (1949)]. The resultsare stated as APR 2.0, which indicates that dosage (in mg./ kg. p.o.) ofan anti-convulsant which brings about double the pentamethylenetetrazole consumption compared with the untreated control group.

The muscle relaxant activity of the compounds of Formula I can, forexample, be demonstrated utilizing the rotating rod test. This testevaluates the ability of mice which are under the influence of a musclerelaxant or sedative compound to hold on to a slowly rotating rod. Therod used has a diameter of 30 mm. and rotates at a speed of tworotations per minute. For the test, those mice are selected which priorto receiving medication could hold on to the rotating rod for at leasttwo minutes. After the mice are selected, these animals are given thecompounds to be tested in various dosages. The animals are then placedon the rotating rod 30 minutes after administration of the compounds.The time for which each of the mice can stay on the rotating rod iscalculated. The dosage which causes a 50 percent reduction of the timethe animals hold on to the rod is designated as the HD The toxicity ofthe compounds of Formula I is illustrated by the indication of the LDThe following table sets forth the results of the testing forrepresentative compounds of Formula I. These test reports relate to thefollowing compounds:

(I) Ethyl (2,3-dihydro-7-nitro-2-oxo-S-phenyl-lH-l ,4-

benzodiazepin-l-yl) methyl] carbamate;

(II) Ethyl [(7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl methyl] carbam ate;

(III) Eethyl{ [7-chloro-5- (2-chlorophenyl -2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-yl]-methyl}carbamate.

The compounds of Formula I can be prepared in the form of variouspharmaceutical preparations which contain them or their salts inadmixture with a pharmaceutical, organic or inorganic inert carriermaterial which is suitable for enteral, percutaneous or parenteralapplication. Suitable carrier materials for this purpose include water,gelatin, gum arabic, lactose, starches magnesium stearate, talc,vegetable oils, polyalkylene glycols, Vaseline, etc. The pharmaceuticalformulations can be prepared in solid form (e.g., as tablets, dragees,suppositories, capsules); in semi-solid form (e.g., as ointments); or inliquid form (e.g., as solutions, suspensions or emulsions). They may besterilized and/or contain additives such as preserving, stabilizing,wetting or emulsifying agents, salts for varying the osmotic pressure orbuffers. They can also contain yet other therapeutically valuablesubstances. The dosage follows individual requirements, but a dosage of0.1 mg./kg. to 5 mg./kg. per day is preferred.

The following examples illustrate the invention. All temperatures arestated in degrees centigrade.

Example 1 A mixture of 14 g. of 1,3-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one, 20 g. of ethyl (N-methyl-N-p-toluenesulphonyloxy)carbamate, 50 ml. of triethylamine and 50 ml. ofdimethylformamide is boiled under reflux for 3 hours. The mixture isthereupon evaporated, initially in vacuum and then under high vacuum,and the residue is partitioned between methylene chloride and 10% sodiumbicarbonate solution. The methylene chloride phase is separated off,washed with sodium carbonate solution and water, dried over sodiumsulfate and evaporated. Chromatography of the residue on 500 g. ofsilica gel with ethyl acetate in methylene chloride yields, aftercrystallization from methylene chlorideether, ethyl[(2,3-dihydro-7-nitro2oxo-S-phenyl-lH-l,4- benzodiazepin-l-yl)methyl]carbamate which melts at 157-160 after recrystallization from methanol.

The ethyl (N-methyl N p-toluenesulphonyloxy)carbamate used as thestarting material can be manufactured as follows:

A solution of 38 g. of p-toluenesulphonyl chloride in 1 00 ml. ofpyridine is added dropwise with ice-cooling and constant stirring to asolution of 24 g. of N-methyl- N-carbethoxyhydroxylamine in 60 ml. ofpyridine, in doing which the reaction temperature should not exceed 5.The mixture is subsequently stirred for a further 4-5 hours at roomtemperature, the major part of the pyridine is removed on the rotaryevaporator at a temperature of 50 and the residue is taken up with ml.of water and 300 ml. of ether. The aqueous phase is separated off; theorganic phase is washed 4 times with 60 ml. of hydrochloric acid eachtime until no more pyridine odor is to be perceived in the wash-water ontreatment with alkali; The organic phase is washed with a further 80 ml.of sodium bicarbonate solution and subsequently dried over sodiumsulfate. After removal of the ether, ethyl(N-methyl-N-p-toluenesulphonyloxy)carbamate remains as a readily mobilecolorless oil which rapidly crystallizes. It is recrystallized fromether/petroleum ether and then melts at 46-47.

Example 2 According to the procedure described in Example 1, from 2.7 g.of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4- benzodiazepin-Z-one, 4.5 g. ofethyl (N-methyl-N-p-toluenesulphonyloxy)carbamate, 10 ml. ofdimethylformamide and 20 ml. of triethylamine there is obtained, afterchromatography on 150 g. of silica gel with 20% acetic ester inmethylene chloride and crystallization from ether/ hexane, ethyl[(7-ch1oro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-l-yl)methyl]carbamate which is recrystallized frommethanol-water and then melts at 126- 129.

Example 3 In analogy to Example 1, by reaction of 6.1 g. of7-chloro-5-(2-chlorophenyl) 1,3-dihydro-2H-1,4-benzodiazepin-Z-one and 9g. of ethyl (N-methyl-N-p-toluene sulphonyloxy)carbamate in 20 ml. ofdimethylformamide and 40 ml. of triethylamine and crystallization fromethanol there is obtained ethyl {[7-chloro-5-(2-chlorophenyl) 2,3dihydro 2 oxo-lH-1,4-benzodiazepin-1-yl] methyl}carbamate. This melts at147-149 after recrystallization from ethanol.

Example 4 A mixture of 2 g. of 7-chloro-1,3-dihydro-5-phenyl-Zil-I-1,4-benzodiazepin-2-one, 4 g. of ethyl (N-benzyl-N-p-tolu'enesulphonyloxy)carbamate, 10 ml. of dimethylformamide and 20 ml.of triethylarnine is boiled under reflux for 4 hours. The mixture issubsequently evaporated and the residue partitioned between water andbenzene. The benzene phase is washed with water, dried over sodiumsulfate and evaporated. The crude product remaining as the residue ischromatographed on 150 g. of silica gel with 10% ethyl acetate inmethylene chloride. The pure fractions crystallize from ether-hexane onstanding in the refrigerator. After recrystallization from ethanol,there is obtained ethyl[a-(7-chloro-2,3-dihydro-2-oxo-5-phenyl-lH-l,4-benzodiazepin 1 yl)benzyl]carbamate of melting point177-170.

The ethyl (N-benzyl-N-p-toluenesulphonyloxy)carbamate used as thestarting product can be manufactured as follows:

31.9 g. of benzylhydroxylamine hydrochloride are treated with ml. of 3 Ncaustic soda, whereby the free base precipitates. This is dissolved in50 ml. of chloroform and, with ice-cooling and powerful stirring, slowlytreated dropwise at ca. 5 with 21.6 g. of chloroformic acid ethyl ester.After completed addition, the ice-bath is removed and the mixture isfurther stirred at room temperature for a further 2 hours. Thechloroform phase is thereafter separated off; the aqueous phase issaturated with sodium chloride and extracted with ether. The combinedorganic phases are dried over sodium sulfate. After evaporating off thesolvent, N-benzyl-N-carbethoxyhy- 7 droxylamine remains as a paleorange-colored oil which is purified by distillation; boiling point130/.0.05 mm. Hg.

A solution of 19.5 g. of the above N-benzyl-N-carbethoxyhydroxylamine in80 ml. of ether is underlayed with a solution of g. of sodium hydroxidein 80 ml. of water. A solution of 19 g. of p-toluenesulphonyl chloridein 80 ml. of ether is thereupon slowly added dropwise with powerfulstirring and with ice-cooling. After completed addition, the ice-bath isremoved and the mixture is further stirred at room temperature for afurther 2 hours. The two phases are then separated, the organic phasedried over sodium sulfate and the ether evaporated off. An orange oilremains which is dissolved in acetone and brought to crystallization atlow temperature (ca. -20). The ethyl (N-benzyl-N-p-toluenesulphonyloxy)carbamate melts at 38-40.

Eaxmple 5 A mixture of 10.8 g. of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 20 g. of crude ethyl (N-ethyl-N-p-toluene-sulphonyloxy)carbamate, 40 ml. of dimethylformamideand 80 ml. of triethylamine is boiled under reflux for 4 hours. Afterevaporation in vacuum, the residue is partitioned between benzene andwater. The benzene phase is washed with water, dried over sodium sulfateand evaporated. Crystallization of the residue from methylene chloride/ether gives back the unreacted starting material. The mother liquor isevaporated. By chromatography of the residue on 250 g. of silica gelwith 20% ethyl acetate in methylene chloride, there is obtained, aftercrystallization from ethanol, pure ethyl [l-(7-chloro-2,3-dihydro-2-ox0-5-phenyl 1H 1,4 benzodiazepin 1 yl) ethyl]carbamate ofmelting point 5-157".

The ethyl (N-ethyl-N-p toluenesulphonyloxy)carbamate used as thestarting product is manufactured in accordance with the data in Examples1 and 4 from N-ethyl- N carbethoxyhydroxylamine and p toluenesulphonylchloride and is further processed as the crude product without priorpurification.

Example 6 An aqueous solution of 1 g. of 2-amino-N-[(ethoxycarbonylaminomethyl] -2-benzoyl-4' chloroacetanilide hydrochloride is made alkalinewith 10% sodium carbonate solution. The base precipitated is extractedwith methylene chloride. The extracts are dried over sodium sulfate andevaporated. The residue is taken up in ethanol and the solution obtainedis boiled under reflux for 10 minutes. The crude product which remainsas the residue after evaporation of the solution is crystallized frommethanol/ water. Ethyl [(7-chloro-2,3-dihydro 2 oxo 5 phenyl-1H-1,4-benzodiazepin-l-yl)methyl]carbamate of melting point 124-2l6 isobtained.

The 2-amino-N [(ethoxycarbonylamino)methyl] 2-benzoyl-4'-chloroacetanilide hydrochloride used as the starting productcan be manufactured as follows:

8.4 g. of 2-benzoyl 2 benzyloxycarbonylamino-4- chloroacetanilide and 9g. of ethyl (N-methyl-N-p-toluenesulphonyloxy)carbamate are boiled underreflux for 3 hours in a mixture of ml. of dimethylformamide and 40 ml.of triethylamine. The reaction mixture is concentrated and thenpartitioned between water and ether. The ether phase is washed withwater, dried over sodium sulphate and evaporated. Chromatography of theresidue on 200 g. of silica gel with 20% ethyl acetate in methylenechloride yields, besides unreacted starting material, pure N-(ethoxycarbonylamino)methyl]-2-benzoyl-2 benzyloxycarbonylamino 4chloroacetanilide as a colorless res1n..

2.1 g. of the above N-[ (ethoxycarbonylamino)methyl]- 2'-benzoyl-2benzyloxycarbonylamino 4' chloroacetanilide are hydrogenated for 45minutes in 30 ml. of ethanol in the presence of 0.5 g. of palladiumcatalyst (5% on charcoal) and 5 mmol of hydrogen chloride. The

mixture is thereupon filtered off the catalyst and concentrated invacuum at 2030. 2 amino N [(ethoxycarbonylamino)methyl] 2 benzoyl 4'chloroacetanalide hydrochloride precipitates as a resin on treatment ofthe residue with ether. The solvent is decanted off and the residuestirred up with ether. The amorphous powder which is obtained onfiltering off by suction is washed with ether and dried in vacuum. Thereis obtained an almost colorless product, the aqueous solution of whichdisplays a pH of ca. 4-5.

Example 7 The following compounds can also be manufactured according tothe process described in Example 6:

ethyl [(2,3-dihydro-7-nitro-2-oxo 5 phenyl 1H 1,4-

benzodiazepin-l yl)methyl]carbamate, melting point 157-160 aftercrystallization from methanol (from 2- amino-N[(ethoxycarbonylamino)methyl] 2 benzoyl-4-nitroacetanilidehydrochloride);

ethyl {[7-chloro-5-(2 chlorophenyl) 2,3 dihydro 2-oxo-lH-1,4-benzodiazepin 1 yl]methyl}carbamate, melting point 147149after crystallization from ethanol (from 2-amino N[(ethoxycarbonylamino) methyl]-4'-chloro 2 (o chlorobenzoyl)acetanilidehydrochloride) ethyl [a-(7-chloro-2,3-dihydro-2 oxo 5 phenyl 1H-1,4-benzodiazepin 1 yl)benzyl]carbamate, melting point 177179 aftercrystallization from ethanol (from Z-amino N [a(ethoxycarbonylamino)benzyl 2- benzoyl-4'-chloroacetanilidehydrochloride); ethyl [1- (7-chloro-2,3-dihydro-2-oxo 5 phenyl 1H 1,4-benzodiazepin 1 yl)ethyl]carbamate, melting point 155l57 aftercrystallization from ethanol (from 2- amino-N-[l(ethoxycarbonylamino)ethyl] 2' benzoyl-4'-chloroacetanilidehydrochloride) Example 8 Tablets of the following composition aremanufactured: Per tablet, mg.

Ethyl [(2,3-dihydro-7-nitro-2-oxo-5-phenyl-1H 1,4-

benzodiazepin-l-yl)methyl]carbamate 10 Corn starch 53 Lactose 150Gelatin (10% solution) 6 The active substance, the corn starch and thelactose are mixed with a 10% gelatin solution. The paste is comminutedand the granulate dried in a suitable pan at 43. The dried granulate isconducted through a comminuting machine and mixed with the followingingredients in a mixer:

Mg. Talc 6 Magnesium stearate 6 Corn starch 9 The mixture is thereuponcompressed to tablets of 450 Example 9 Suppositories are manufacturedwith the following ingredients:

Per 1.3 g. suppository, g. Ethyl [(2,3-dihydro-7-nitro-2-oxo-5 phenyl1H- 1,4-benzodiazepin-1-yl)methyl]carbamate 0.025 Cocoa butter (meltingpoint 36-37) 1.230 Carnauba wax 0.045

9 Example 10 A parenteral formulation is manufactured with the followingingredients:

Per. ml. Ethyl (2,3-dihydro-7-nitro-2-oxo-S-phenyl-1H-1,4-

benzodiazepin-l-yl)methyl]carbamate. 5 mg. Dimethylacetamide 10%.Propylene glycol 50%. Benzyl alcohol 1.5%. Ethanol 10%. Water forinjection, q.s. ad 1 ml.

The active substance is dissolved in the dimethylacetamide, benzylalcohol, propylene glycol, ethanol and water are added, the mixture isfiltered through a candle filter and the filtrate is filled into ampulesof a suitable size. The ampules are thereupon sealed and sterilized.

Example 11 Tablets and suppositories and a parenteral formulation aremanufactured according to the processes described in Examples 8 to 10,but ethyl [(7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-yl)methyl] carbamate or ethyl{[7-chloro-5-(2-chlorophenyl) 2,3 dihydro-Z-oxo-1H-1,4-benzodiazepin-1-y1]methyl}carbamate is used as wherein Rsignifies halogen or nitro; R signifies hydrogen or halogen; R signifieshydrogen, lower alkyl or phenyl, halo-phenyl and lower alkyl-phenyl; andR signifies lower alkyl and the pharmaceutically acceptable acidaddition salts thereof.

2. A compound of claim 1 wherein the R substituent is nitro and is inthe 7-position of the benzodiazepine moiety.

3. The compound of claim 2 wherein R and R are hydrogen and R is ethyl,i.e., a compound of the formula ethyl [(2,3 dihydro 7 nitro 2 x0 phenyl1H- 1,4-benzodiazepin-1-yl) methyl] carbamate.

4. A compound of Formula 1 wherein the R substituent is chlorine and isin the 7-position of the benzodiazepine moiety.

5. The compound of claim 4 wherein R and R are hydrogen and R is ethyl,i.e., a compound of the formula ethyl [(7-chloro-2,3-dihydro-2-oxo 5phenyl 1H-1,4- benzodiazepinl-yl) methyl] carbamate.

6. The compound of claim 4 wherein R is chlorine and is in the2'-position of the benzodiazepine moiety, R is hydrogen and R is ethyl,i.e., a compound of the formula ethyl[(7-chloro 5 (2 chlorophenyl) 2,3dihydro- 2 0x0 1H-1,4-benzodiazepin-1-yl)methylJcarbamate.

7. The compound of claim 4 wherein R is hydrogen, R is phenyl and R isethyl, Le, a compound of the formula ethyl[a-(7-chl0ro-2,3-dihydro-2-oxo-5-phenyl- 1H-1,4-benzodiazepin-1-yl)benzyl] carbamate.

8. The compound of claim 4 wherein R is hydrogen, R is methyl and R isethyl, i.e., a compound of the 5 formula ethyl[1-(7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benZodiazepin-1-yl)ethyl]carbamate.

9. A.process for preparing a compound of the formula NHOOOR4 10 CH-RaNO=O wherein R slgnlfies halogen or mtro; R signifies hydrogen orhalogen; R signifies hydrogen, lower alkyl or phenyl, halo-phenyl andlower alkyl-phenyl; and R signifies lower alkyl which comprises reactinga compound of the formula H NC=O wherein R and R are as described abovewith a compound of the formula wherein R and R are as described aboveand R signifies lower alkyl or phenyl, halo-phenyl and lower alkylphenylin the presence of a base.

References Cited R. T. BOND, Assistant Examiner US. Cl. X.R.

260470, 470 A; 424244; 26048l C, 471 C, 482 C, 562 N

